Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents

Abstract

In one aspect, the present disclosure provides new analogs of uncialamycin of formulae (I) and (II). The present disclosure also provides novel synthetic pathways to obtaining uncialamycin and analogs thereof. Additionally, the present disclosure also describes methods of use of uncialamycin and analogs thereof. In another aspect, the present disclosure provides antibody-drug conjugates comprising the compounds of formulae (I) and (II).

The invention claimed is: 
     
       1. A compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y 1  is —O(CH 2 ) m Y′, —NH(CH 2 ) m Y′, —S(CH 2 ) m Y′, or —(CH 2 ) m NR 1 R 2 , or is taken together with Z 1  as defined below; 
 wherein:
 Y′ is hydroxy, halo, mercapto, alkyl (C1-12) , substituted alkyl (C1-12) , alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , acyl (C≦12) , substituted acyl (C1-12) , acyloxy (C1-12) , substituted acyloxy (C1-12) , alkylamino (C1-12) , or substituted alkylamino (C1-12) ; 
 m is 1, 2, 3, 4, 5, or 6; and 
 R 1  and R 2  are each independently selected from hydrogen, hydroxy, alkyl (C1-12) , substituted alkyl (C1-12) , alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , aryl (C6-12) , substituted aryl (C6-12) , aralkyl (C7-12) , substituted aralkyl (C7-12) , heteroaryl (C1-12) , substituted heteroaryl (C1-12) , heterocycloalkyl (C2-12) , substituted heterocycloalkyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , acyloxy (C1-12) , substituted acyloxy (C1-12) , alkylamino (C1-12) , substituted alkylamino (C1-12) ; a monovalent amine protecting group, —C(O)O(CH 2 ) n S-A 1 , —C(O)O(CH 2 ) n S(O)-A 1 , or —C(O)O(CH 2 ) n S(O) 2 -A 1 , 
 wherein:
 A 1  is aryl (C6-12) , substituted aryl (C6-12) , or 
 
 
 
       
         
           
           
               
               
           
         
         
           
             wherein:
 A 2  is alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , acyloxy (C1-12) , substituted acyloxy (C1-12) , alkoxy (C1-12) , substituted alkoxy (C1-12) , alkylamino (C1-12) , substituted alkylamino (C1-12) , dialkylamino (C2-12) , or substituted dialkylamino (C2-12) ; wherein A 2  is not —CO 2 H, —CO 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)CH 3 , —NHCH 3 , —NHCH 2 CH 3 , —N(CH 3 ) 2 , —C(O)NH 2 , and —OC(O)CH 3 ; and 
 
             n is 1, 2, 3, 4, or 5; or 
           
           R 1  and R 2  are taken together and are divalent amine protecting group, alkanediyl (C1-12) , alkylaminodiyl (C1-8) ; alkoxydiyl (C1-8) ; or a substituted version of either of these groups; or 
           Y 1  is taken with Z 1  and is alkylaminodiyl (C1-8)  substituted alkylaminodiyl (C1-8) ; -alkanediyl (C1-6) -NZ 2 -alkanediyl (C1-6) , or -substituted alkanediyl (C1-6) -NZ 2 -substituted alkanediyl (C1-6) , 
           wherein:
 Z 2  is hydrogen, an amine protecting group, acyl (C6-12) , substituted acyl (C6-12) , —C(O)O(CH 2 ) n S-A 3 , or —C(O)O(CH 2 ) n S(O) 2 -A 3 , and 
 wherein:
 A 3  is aryl (C6-12) , substituted aryl (C6-12) , or 
 
 
         
       
       
         
           
           
               
               
           
         
         
           
             
               wherein: 
                A 4  is alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , acyloxy (C1-12) , substituted acyloxy (C1-12) , alkoxy (C1-12) , substituted alkoxy (C1-12) , alkylamino (C1-12) , substituted alkylamino (C1-12) , dialkylamino (C2-12) , or substituted dialkylamino (C2-12) , wherein A 4  is not —CO 2 H, —CO 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)CH 3 , —NHCH 3 , —NHCH 2 CH 3 , —N(CH 3 ) 2 , —C(O)NH 2 , and —OC(O)CH 3 ; 
             
           
         
         Z 1  is absent, hydrogen or taken together with Y 1  as defined above; 
         R 3  and Z 2  are each independently selected from hydrogen, hydroxy, halo, amino, cyano, nitro, phosphate, or mercapto, or
 alkyl (C1-12) , alkenyl (C2-12) , alkynyl (C2-12) , aryl (C6-12) , aralkyl (C7-12) , heteroaryl (C1-12) , heterocycloalkyl (C2-12) , acyl (C1-12) , alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , amido (C1-12) , or a substituted version of any of these groups; 
 
         o is 1, 2, or 3; 
         R 4  is hydrogen, alkyl (C1-12) , a monovalent amine protecting group, or substituted alkyl (C1-12) ; 
         R 5 , R 6 , and R 7  are each independently hydrogen, hydroxy, amino, mercapto, —OX 1 , —NX 2 X 3 , or —SX 4 ; or
 alkyl (C1-12) , alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C2-12) , alkylthio (C1-12) , amido (C1-12) , or a substituted version of any of these groups; 
 wherein:
 X 1  is a hydroxy protecting group; 
 X 2  and X 3  are independently selected from hydrogen, a monovalent amine protecting group, or when X 2  and X 3  are taken together form a divalent amine protecting group; and 
 X 4  is a thiol protecting group; 
 
 
         R 8  is hydroxy, amino, or mercapto; or 
         alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , alkylthio (C1-12) , amido (C1-12) , or a substituted version of any of these groups; and 
         R 9 , R 10 , R 11 , and R 12  are each independently selected from hydrogen, hydroxy, amino, mercapto, —OX 1 , —NX 2 X 3 , or —SX 4 , or
 alkyl (C1-12) , alkenyl (C2-12) , alkynyl (C2-12) , aryl (C6-12) , aralkyl (C7-12) , heteroaryl (C1-12) , heterocycloalkyl (C2-12) , acyl (C1-12) , alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , alkylthio (C1-12) , amido (C1-12) , or a substituted version of any of these groups; or Y 2 —R 13 ; 
 wherein:
 X 1  is alkyl (C1-12) , substituted alkyl (C1-12) , alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , aryl (C6-12) , substituted aryl (C6-12) , aralkyl (C7-12) , substituted aralkyl (C7-12) , heteroaryl (C1-12) , substituted heteroaryl (C1-12) , heterocycloalkyl (2-12) , substituted heterocycloalkyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , or a hydroxy protecting group; 
 X 2  and X 3  are independently selected from hydrogen, alkyl (C1-12) , substituted alkyl (C1-12) , alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , aryl (C6-12) , substituted aryl (C6-12) , aralkyl (C7-12) , substituted aralkyl (C7-12) , heteroaryl (C1-12) , substituted heteroaryl (C1-12) , heterocycloalkyl (C2-12) , substituted heterocycloalkyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , a monovalent amine protecting group, or when X 2  and X 3  are taken together form a divalent amine protecting group; 
 X 4  is alkyl (C1-12) , substituted alkyl (C1-12) , alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , aryl (C6-12) , substituted aryl (C6-12) , aralkyl (C7-12) , substituted aralkyl (C7-12) , heteroaryl (C1-12) , substituted heteroaryl (C1-12) , heterocycloalkyl (C2-12) , substituted heterocycloalkyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , or a thiol protecting group; 
 Y 2  is alkanediyl (C1-12)  or substituted alkanediyl (C1-12) ; and 
 R 13  is hydroxy, amino, mercapto, —OX 1 , —NX 2 X 3 , or —SX 4 , or heteroaryl (C1-12) , heterocycloalkyl (C2-12) , acyl (C1-12) , alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , alkylthio (C1-12) , amido (C1-12) , or a substituted version of any of these groups; 
 
 
         p and q are each independently 1 or 2; and 
         Z 3  is hydrogen, hydroxy, halo, amino, cyano, nitro, phosphate, or mercapto, or
 alkyl (C1-12) , alkenyl (C2-12) , alkynyl (C2-12) , aryl (C6-12) , aralkyl (C7-12) , heteroaryl (C1-12) , heterocycloalkyl (C2-12) , acyl (C1-12) , alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , amido (C1-12) , or a substituted version of any of these groups; 
 
         provided that Y 1  is not —NHMe or —NHCH 2 CH 2 NH 2 ; or 
       
       a pharmaceutically acceptable salt thereof. 
     
     
       2. The compound of  claim 1 , wherein the formula is further defined as: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y 1  is —O(CH 2 ) m Y′, —NH(CH 2 ) m Y′, —S(CH 2 ) m Y′, or —(CH 2 ) m NR 1 R 2 , or taken together with Z 1  as described below; 
 wherein:
 Y′ is hydroxy, halo, mercapto, alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , acyl (C≦12) , substituted acyl (C1-12) , acyloxy (C1-12) , substituted acyloxy (C1-12) , alkylamino (C1-12) , or substituted alkylamino (C1-12) ; 
 m is 1, 2, 3, 4, 5, or 6; and 
 R 1  and R 2  are each independently selected from hydrogen, hydroxy, alkyl (C1-12) , substituted alkyl (C1-12) , alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , aryl (C6-12) , substituted aryl (C6-12) , aralkyl (C7-12) , substituted aralkyl (C7-12) , heteroaryl (C1-12) , substituted heteroaryl (C1-12) , heterocycloalkyl (C2-12) , substituted heterocycloalkyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , acyloxy (C1-12) , substituted acyloxy (C1-12) , alkylamino (C1-12) , substituted alkylamino (C1-12) ; a monovalent amine protecting group, —C(O)O(CH 2 ) n S-A 1 , —C(O)O(CH 2 ) n S(O)-A 1 , or —C(O)O(CH 2 ) n S(O) 2 -A 1 , 
 wherein:
 A 1  is aryl (C6-12)  or substituted aryl (C6-12) ; and 
 n is 1, 2, 3, 4, or 5; 
 
 R 1  and R 2  are taken together and are a divalent protecting group, alkanediyl (C≦12) , alkylaminodiyl (C≦8) ; alkoxydiyl (C≦8) ; or a substituted version of either of these groups; or 
 
 Y 1  is taken with Z 1  and is alkylaminodiyl (C1-8)  substituted alkylaminodiyl (C1-8) ; or -alkanediyl (C1-6) -NZ 2 -alkanediyl (C1-6) ,
 wherein:
 Z 2  is hydrogen, an amine protecting group, acyl (C6-12) , substituted acyl (C6-12) , —C(O)O(CH 2 ) n S-A 3 , or —C(O)O(CH 2 ) n S(O) 2 -A 3 , 
 wherein:
 A 3  is aryl (C6-12)  or substituted aryl (C6-12) ; 
 
 
 
 Z 1  is absent, hydrogen or taken together with Y 1  as defined above; 
 R 3  is hydrogen, hydroxy, halo, amino, cyano, nitro, phosphate, or mercapto, or
 alkyl (C1-12) , alkenyl (C2-12) , alkynyl (C2-12) , aryl (C6-12) , aralkyl (C7-12) , heteroaryl (C1-12) , heterocycloalkyl (C2-12) , acyl (C1-12) , alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , amido (C1-12) , or a substituted version of any of these groups; 
 
 o is 1, 2, or 3; 
 R 4  is hydrogen, alkyl (C1-12) , a monovalent amine protecting group, or substituted alkyl (C1-12) ; 
 R 5 , R 6 , and R 7  are each independently hydrogen, hydroxy, amino, mercapto, —OX 1 , —NX 2 X 3 , or —SX 4 ; or
 alkyl (C1-12) , alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , alkylthio (C1-12) , amido (C1-12) , or a substituted version of any of these groups; 
 wherein:
 X 1  is a hydroxy protecting group; 
 X 2  and X 3  are independently selected from hydrogen, a monovalent amine protecting group, or when X 2  and X 3  are taken together form a divalent amine protecting group; and 
 X 4  is a thiol protecting group; and 
 
 
 R 8  is hydroxy, amino, or mercapto; or 
 alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , alkylthio (C1-12) , amido (C1-12) , or a substituted version of any of these groups; or 
 
       a pharmaceutically acceptable salt thereof. 
     
     
       3. The compound of  claim 1 , wherein the formula is further defined as: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are each independently selected from hydrogen, hydroxy, 
 alkyl (C1-12) , substituted alkyl (C1-12) , alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , aryl (C6-12) , substituted aryl (C6-12) , aralkyl (C7-12) , substituted aralkyl (C7-12) , heteroaryl (C1-12) , substituted heteroaryl (C1-12) , heterocycloalkyl (C2-12) , substituted heterocycloalkyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , acyloxy (C1-12) , substituted acyloxy (C1-12) , alkylamino (C1-12) , substituted alkylamino (C1-12) ; a monovalent amine protecting group, —C(O)O(CH 2 ) n S-A 1 , —C(O)O(CH 2 ) n S(O)-A 1 , or —C(O)O(CH 2 ) n S(O) 2 -A 1 , 
 wherein:
 A 1  is aryl (C6-12)  or substituted aryl (C6-12) ; and 
 n is 1, 2, 3, 4, or 5; 
 
 R 3  is hydrogen, hydroxy, halo, or alkoxy (C1-12)  or substituted alkoxy (C1-12) ; 
 o is 1, 2, or 3; 
 R 4  is hydrogen, a monovalent amine protecting group, alkyl (C1-12) , or substituted alkyl (C1-12) ; 
 R 5 , R 6 , and R 7  are each independently hydrogen, hydroxy, amino, mercapto, —OX 1 , —NX 2 X 3 , or —SX 4 ; or 
 alkyl (C1-12)  or substituted alkyl (C1-12) ;
 wherein: 
 X 1  is a hydroxy protecting group; 
 X 2  and X 3  are independently selected from hydrogen, a monovalent amine protecting group, or when X 2  and X 3  are taken together form a divalent amine protecting group; and 
 X 4  is a thiol protecting group; and 
 
 R 8  is hydroxy, amino, or mercapto; or 
 
       a pharmaceutically acceptable salt thereof. 
     
     
       4. The compound of  claim 1 , wherein the formula is further defined as: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are each independently selected from hydrogen, hydroxy, 
 alkyl (C1-12) , substituted alkyl (C1-12) , aryl (6-12) , substituted aryl (C6-12) , aralkyl (C7-12) , substituted aralkyl (C7-12) , acyl (C1-12) , substituted acyl (C1-12) , a monovalent amine protecting group, —C(O)O(CH 2 ) n S—C 6 H 5 , —C(O)O(CH 2 ) n S(O)—C 6 H 5 , or —C(O)O(CH 2 ) n S(O) 2 —C 6 H 5 , 
 a monovalent amine protecting group, or R 1  and R 2  are taken together and form a divalent amine protecting group, or 
 alkyl (C1-12) , aryl (C6-12) , aralkyl (C7-12) , acyl (C1-12) , or a substituted version of any of these groups; 
 R 3  is hydrogen, hydroxy, halo, or 
 alkoxy (C1-12)  or substituted alkoxy (C1-12) ; and 
 o is 1, 2, or 3; or 
 
       a pharmaceutically acceptable salt thereof. 
     
     
       5. The compound of  claim 1 , wherein the formula is further defined as: 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1  is a hydroxy protecting group; 
 R 1  and R 2  are each independently selected from hydrogen, alkyl (C1-12) , or substituted alkyl (C1-12) ; and 
 R 3  is hydrogen, alkoxy (C1-12) , or substituted alkoxy (C1-12) ; and 
 o is 2; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       6. The compound of  claim 1 , wherein Y 1  is —(CH 2 ) m NR 1 R 2 . 
     
     
       7. The compound of  claim 1 , wherein m is 1, 2, or 3. 
     
     
       8. The compound of  claim 1 , wherein R 1  or R 2  is hydrogen, alkyl (C1-12)  or substituted alkyl (C1-12) . 
     
     
       9. The compound of  claim 1 , wherein R 3  is hydrogen. 
     
     
       10. The compound of  claim 1 , wherein the compound is further defined as: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       11. The compound of  claim 1 , further defined as: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       12. A conjugate of the formula:
   (A 5 -L) r -A 6   (XVII)
 
 
       wherein:
 A 5  is a compound of  claim 1 ; 
 L is a linker; 
 r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and 
 A 6  is a cell targeting moiety. 
 
     
     
       13. The conjugate of  claim 12 , wherein L comprises a polypeptide cleavable by an intracellular enzyme. 
     
     
       14. The conjugate of  claim 13 , wherein the enzyme is cathepsin B. 
     
     
       15. The conjugate of  claim 12 , wherein L comprises a self-immolating group. 
     
     
       16. The conjugate of  claim 12 , wherein A 6  is an antibody whose antigen is a tumor associated antigen. 
     
     
       17. The conjugate of  claim 16 , wherein the antigen is mesothelin, glypican-3, or CD70 and the antibody is an anti-mesothelin, anti-glypican-3, or anti-CD70 antibody. 
     
     
       18. The conjugate of  claim 12 , wherein A 5  is a compound according to formula I. 
     
     
       19. The conjugate of  claim 12 , further comprising a structure of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 A 6  is an antibody and r is 1, 2, 3, or 4. 
 
     
     
       20. The compound of  claim 11  further defined as: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       21. The compound of  claim 11  further defined as: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.